Drug delivery device

ABSTRACT

The invention relates to a reusable drug delivery device for selecting and dispensing a number of user variable doses of a medicament. The device comprises a housing, a cartridge holder for retaining a cartridge containing the medicament, a piston rod displaceable relative to the cartridge holder, a driver coupled to the piston rod, a display member for indicating a set dose and being coupled to the housing and to the driver, and a button coupled to the display member and to the driver.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application pursuant to35 U.S.C. §371 of International Application No. PCT/EP2013/067860 filedAug. 29, 2013, which claims priority to European Patent Application No.12182564.0 filed Aug. 31, 2012, and U.S. Provisional Patent ApplicationNo. 61/696,496, filed Sep. 4, 2012. The entire disclosure contents ofthese applications are herewith incorporated by reference into thepresent application.

TECHNICAL FIELD

The present invention is generally directed to drug delivery devices.More particularly, the present invention is directed to reusable drugdelivery devices.

BACKGROUND

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This may beincreasingly common among patients having diabetes where self-treatmentenables such patients to conduct effective management of their disease.In practice, such a drug delivery device allows a user to individuallyselect and dispense a number of user variable doses of a medicament. Thepresent invention is not directed to so called fixed dose devices whichonly allow dispensing of a predefined dose without the possibility toincrease or decrease the set dose.

There are basically two types of drug delivery devices: resettabledevices (i.e., reusable) and non-resettable (i.e., disposable). Forexample, disposable pen delivery devices are supplied as self-containeddevices. Such self-contained devices do not have removable pre-filledcartridges. Rather, the pre-filled cartridges may not be removed andreplaced from these devices without destroying the device itself.Consequently, such disposable devices need not have a resettable dosesetting mechanism.

These types of pen delivery devices (so named because they oftenresemble an enlarged fountain pen) are generally comprised of threeprimary elements: a cartridge section that includes a cartridge oftencontained within a housing or holder; a needle assembly connected to oneend of the cartridge section; and a dosing section connected to theother end of the cartridge section. A cartridge (often referred to as anampoule) typically includes a reservoir that is filled with a medication(e.g., insulin), a movable rubber type bung or stopper located at oneend of the cartridge reservoir, and a top having a pierceable rubberseal located at the other, often necked-down, end. A crimped annularmetal band is typically used to hold the rubber seal in place. While thecartridge housing may be typically made of plastic, cartridge reservoirshave historically been made of glass.

The needle assembly is typically a replaceable double-ended needleassembly. Before an injection, a replaceable double-ended needleassembly is attached to one end of the cartridge assembly, a dose isset, and then the set dose is administered. Such removable needleassemblies may be threaded onto, or pushed (i.e., snapped) onto thepierceable seal end of the cartridge assembly.

The dosing section or dose setting mechanism is typically the portion ofthe pen device that is used to set a dose. During an injection, aspindle or piston rod contained within the dose setting mechanismpresses against the bung or stopper of the cartridge. This force causesthe medication contained within the cartridge to be injected through anattached needle assembly. After an injection, as generally recommendedby most drug delivery device and/or needle assembly manufacturers andsuppliers, the needle assembly is removed and discarded.

For reusable drug delivery devices it is necessary to allow the pistonrod or lead screw to be reset, i.e. pushed and/or wound back into thedevice, during the step of replacing an empty cartridge by a new (full)cartridge. In addition, many drug delivery devices comprise a doselimiter for preventing the setting of a dose, which exceeds the amountof liquid left in a cartridge of the drug delivery device. If such adose limiter is provided, this dose limiter mechanism has to be reset,too.

In the following resetting of the device is to be understood the act ofreplacing or exchanging a cartridge involves a retraction of the pistonrod or lead screw and, if present, bringing the dose limiter (last doseprotection mechanism) back into an initial configuration allowing dosesetting.

It is an object of the present invention to provide an improved reusabledrug delivery device.

SUMMARY

According to a first embodiment of the present invention, this object issolved by a drug delivery device for selecting and dispensing a numberof user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, a clutch forrotationally coupling the driver to the housing or the display memberand a button rotationally coupled to the display member and to thedriver, wherein the driver is in threaded engagement with the pistonrod, permanently rotationally locked to the button, axially displaceablerelative to the button and comprises at least two separate componentswhich are rotationally coupled during dose setting and during dosedispensing and which are rotationally decoupled during resetting of thedevice. Decoupling of the two driver components during resetting has thebenefit that both, the piston rod, which is in threaded engagement withthe driver, and a dose limiter mechanism, which usually acts on thedriver, can be reset together by spinning one of the driver componentswhereas the other remains stationary in the device. The driver maycomprise a third component for coupling the first and second componentsduring dose setting and dose dispensing.

According to a second embodiment of the present invention, this objectis solved by a drug delivery device for selecting and dispensing anumber of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, a clutch forrotationally coupling the driver to the housing or the display memberand a button rotationally coupled to the display member and to thedriver, wherein the display member has a distal end provided with aninwardly protruding thread and a proximal end provided with an inwardlyprotruding flange, wherein the display member comprises two separatecomponents with a first component comprising the thread and the othercomponent comprising the flange. The display member has to be coupled tothe housing and to the driver. The construction of the display memberwith two inwardly directed engaging features avoids a bulky design ofthe device which would be the result if one engagement feature would beon the outside and the other would be on the inside of the displaymember. In addition, the inwardly directed engagement features make itpossible to provide further functions on the outer surface of thedisplay member, e.g. limiting stop elements. Providing two separatecomponents, which are preferably axially and rotationally constrained,makes production of the display member more efficient and easier.Preferably, the display member has a series of numbers or the likesymbols arranged on its outer surface for indicating a set dose. If thedisplay member is in threaded engagement with the housing, the numbersor the like may be arranged on a helical path.

According to a third embodiment of the present invention, this object issolved by a drug delivery device for selecting and dispensing a numberof user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, a clutch forrotationally coupling the driver to the housing or the display memberand a button rotationally coupled to the display member and to thedriver, wherein the button comprises fingers which engage correspondingslots of the driver for rotationally coupling the button to the driverand which comprise snap features engaging corresponding snap features ofthe clutch for axially coupling the button to the clutch. In otherwords, the driver and the button are rotationally coupled by a dogclutch or claw coupling with the fingers of the button having theadditional function of axially constraining the button to the clutchmember. This additional function in one component reduces the number ofcomponent parts of the device and assembling complexity.

According to a fourth embodiment of the present invention, this objectis solved by a drug delivery device for selecting and dispensing anumber of user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, a clutch forrotationally coupling the driver to the housing or the display memberand a button rotationally coupled to the display member and to thedriver, wherein the driver comprises fingers which engage correspondingslots of the button for rotationally coupling the button to the driverand which comprise hook features engaging corresponding contact featuresof the display member for axially coupling the driver to the displaymember. In other words, the driver and the button are rotationallycoupled by a dog clutch or claw coupling with the fingers of the driverhaving the additional function of axially engaging the display member,e.g. for entraining the display member during dose dispensing. Thisadditional function in one component reduces the number of componentparts of the device and assembling complexity.

According to a fifth embodiment of the present invention, this object issolved by a drug delivery device for selecting and dispensing a numberof user variable doses of a medicament, comprising a housing, acartridge holder for retaining a cartridge containing the medicament, apiston rod displaceable relative to the cartridge holder, a drivercoupled to the piston rod, a display member for indicating a set doseand being coupled to the housing and to the driver, a clutch forrotationally coupling the driver to the housing or the display memberand a button rotationally coupled to the display member and to thedriver, wherein the button comprises a ring of clicker teeth engaging acorresponding clicker feature of the display member at least during dosedispensing. The clicker produces a tactile and/or audible feedbackduring use of the device and is usually provided with at least oneseparate component. In the present embodiment of the invention, thesefunctions of the device are realized without adding component parts.Preferably, the display member comprises an elastically deformablefinger having a protrusion for engaging the clicker teeth. An additionalclicker may be provided, which is active during dose setting.

Preferably, the piston rod is a double threaded piston rod having afirst outer thread engaging an internal thread of the housing and asecond outer thread engaging an internal thread of the driver, whereinthe first and second outer threads may overlap each other at leastpartially. This allows providing a mechanical advantage, i.e. atransmission (gear) ratio, in the device. Typically, the dial extensionof the button, i.e. the distance the button winds out of the housingduring dose setting, will be larger than the distance the piston rod isdisplaced relative to the cartridge holder and thus the cartridge. Thisallows dispensing even small amounts of a medicament with a maximum ofdispensing control by the user. The first and second outer threads mayhave a different pitch. However, it is preferred if the first and secondouter threads have the same pitch but are oppositely directed.

One of the outer threads of the piston rod may be in engagement with acorresponding inner thread of the housing, preferably an inner housingbody. Thus, the piston rod rotates both, during dose dispensing andduring resetting of the device, .i.e. when the piston rod is pushed(wound) back.

A further reduction of the number of component parts may be achieved ifthe piston rod comprises a bearing attached to the piston rod by atleast one predefined breakage point. The bearing is axially constrainedbut rotatable with respect to the piston rod after detachment of thebearing by destroying the at least one predefined breakage point duringor after assembly. Thus, only one single component has to be handledduring assembly which in use fulfils the function of two separatecomponents.

According to a preferred embodiment, the driver is a tubular elementhaving a distal portion engaging a nut interposed between the housingand the driver, and a proximal portion which at least partly surrounds atubular portion of the button. Preferably, one of the housing and thedriver comprises at least one spline and the other of the housing andthe driver comprises a threaded portion with the nut interposed betweenthe housing and the driver, wherein the nut comprises at least oneprotrusion engaging the at least one spline and a thread engaging thethreaded portion, and wherein the threaded portion of the housing or thedriver comprises a rotational end stop. If the nut abuts the rotationalend stop, further movement of the nut in the thread is prevented whichthus prevents further rotation of the driver relative to the housingwhich is required during dose setting. Thus, the nut may be used tolimit the settable dose. This is e.g. required to prevent setting a doseexceeding the amount of medicament in the cartridge.

Preferably, the housing comprises an outer body and an inner body withthe cartridge holder being releasably coupled to the inner body. Theinner body may be rotationally and axially constrained within the outerbody such that a cylindrical gap exists between the inner body and theouter body. Preferably, the inner body comprises an outer threadengaging an inner thread of the display member and comprises at leastone inner spline engaging a protrusion of a clicker and/or a doselimiter nut.

In a standard embodiment, the splines of the inner body are axiallyaligned with the pen device. In an alternative embodiment, it ispossible to reduce dispense force, increase the velocity ratio and toincrease the thread pitch of the display member (i.e. increase offriction coefficient asymptote), by providing the inner body with atleast one inner spline which is helically twisted. In other words, thesplines are not axially aligned, which results in the driver and thebutton traveling helically during dose dispensing. This may requireadding an over-cap for the button as an additional component preventingrelative rotation with respect to a user's hand, typically the thumb,during dose dispensing.

If the driver comprises a first component which is in threadedengagement with a nut and a second component, the first and the secondcomponents may be operatively coupled together in a releasable manner.It is preferred that when a user sets a dose by rotating the button,both the first component and the second component of the driver rotatetogether. Further, when a user resets the device, the first component ofthe driver is preferably decoupled from the second component of thedriver and the first component is allowed to rotate with respect to thehousing and with respect to the second component. The nut may be part ofa dose limiter for preventing the setting of a dose, which exceeds theamount of liquid left in a cartridge of the drug delivery device. Thus,a simple and yet reliable resetting mechanism is provided by splittingthe driver into two components.

The precision of a last dose protection mechanism, i.e. a dose limiterfor preventing the setting of a dose, which exceeds the amount of liquidleft in a cartridge of the drug delivery device, may be increased by thedriver being in threaded engagement with a nut, and the threadedengagement comprises a helical groove having a first pitch providedalong a first portion of the driver, a second pitch provided along asecond portion of the driver wherein the first pitch is smaller than thesecond pitch, and, optionally, a third pitch provided along a thirdportion of the driver wherein the third pitch is smaller than the secondpitch. Preferably, the second and third portions are located close to arotational hard stop limiting further movement of the nut for preventingthe setting of a dose, which exceeds the amount of liquid left in acartridge of the drug delivery device. The pitch of the first portionmay be selected small to reduce the axial length of the device. Theincreased pitch of the second portion results in a higher axialdisplacement of the nut relative to the driver such that the nut maypass a relatively large and thus robust rotational hard stop.

The drug delivery device may further comprise a clicker producing atactile and/or audible feedback during dose setting, i.e. increasing orreducing the dose. This additional clicker may include a first toothedelement rotationally constrained to the housing, a second toothedelement rotationally constrained to the driver and a spring biasing thefirst toothed element and the second toothed element into engagement.

A transparent window may be provided within the housing for allowing auser to view the numbers or the like on the display member indicatingthe set dose. Preferably, the housing comprises an inner body and anouter body with the window being attached to the housing by firstretaining means of the inner body and second retaining means of theouter body.

The basic function of the drug delivery device according to the presentinvention may include that a dose is selected by rotating a buttoncomponent, which travels helically during dose setting. A dose may bedelivered by pressing on the same button component, which now movesaxially during dispensing. Preferably, any dose size can be selected, inpredefined increments, between zero and a predefined maximum dose, e.g.80 units. It is a further advantage if the mechanism permits cancellingof a dose without medicament being dispensed, e.g. by rotation of thebutton component in the opposite direction to when selecting a dose.

It is preferred if during dose setting the button is rotated whichentrains the driver and the display member such that the button, thedriver and the display member are moved on a helical path with respectto the housing and the piston rod. Further, during dose dispensing thebutton is axially displaced which entrains the driver and the displaymember such that the button, the driver and the display member areaxially moved with respect to the housing and the piston rod, with thedisplay member and the piston rod rotating with respect to the housing,the button and the driver.

To prevent malfunction or misuse of the device, the dose settingmechanism may be provided with stops preventing dialling of a dose belowzero units or dialling of a dose above a maximum dose. Preferably,rotational hard stops are provided, e.g. between the display member andthe housing as a zero unit stop and/or as a maximum units stop. If thehousing comprises an inner body and an outer body, a first rotationalstop may be provided between the inner body and the display member and asecond rotational stop may be provided between the outer body and thedisplay member for limiting the rotational movement of the displaymember relative to the housing. The minimum dose, usually zero units,may be defined by the first rotational stop and the maximum dose, e.g.60, 80 or 120 units, may be defined by the second rotational stop.

The drug delivery device may comprise a cartridge containing amedicament. The term “medicament”, as used herein, means apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 Exendin-4(1-39),-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   wherein the group -Lys6-NH2 may be bound to the C-terminus of the    Exendin-4 derivative;-   or an Exendin-4 derivative of the sequence-   des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2;-   or a pharmaceutically acceptable salt or solvate of any one of the    afore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two 0 sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; a and y containapproximately 450 amino acids and δ approximately 500 amino acids, whileα and γ have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H-H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

BRIEF DESCRIPTION OF THE FIGURES

A non-limiting, exemplary embodiment of the invention will now bedescribed with reference to the accompanying drawings, in which:

FIG. 1 shows a drug delivery device with a cap attached in accordancewith the present invention;

FIG. 2 shows the drug delivery device of FIG. 1 with the cap removed anda dose of 79 units dialed;

FIG. 3 shows in an exploded view the components of the drug deliverydevice of FIG. 1;

FIG. 4 shows the outer body of the drug delivery device of FIG. 1;

FIG. 5 a shows the inner body of the drug delivery device of FIG. 1;

FIG. 5 b shows a detail of the inner body of FIG. 5 a;

FIG. 6 shows the cartridge holder of the drug delivery device of FIG. 1;

FIG. 7 a shows a first display member component of the drug deliverydevice of FIG. 1;

FIG. 7 b shows a detail of the first display member of FIG. 7 a;

FIG. 8 shows a second display member component of the drug deliverydevice of FIG. 1;

FIG. 9 shows a first driver component of the drug delivery device ofFIG. 1;

FIG. 10 shows a second driver component of the drug delivery device ofFIG. 1;

FIG. 11 shows a third driver component of the drug delivery device ofFIG. 1;

FIG. 12 shows the last dose nut of the drug delivery device of FIG. 1;

FIG. 13 shows a clutch component of the drug delivery device of FIG. 1;

FIG. 14 shows a first clicker component of the drug delivery device ofFIG. 1;

FIG. 15 shows a second clicker component of the drug delivery device ofFIG. 1;

FIG. 16 shows the button of the drug delivery device of FIG. 1;

FIG. 17 shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a zero unit position with the button released;

FIG. 18 shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a position with some units dialed; and

FIG. 19 shows a cut-away view of the proximal part of the drug deliverydevice of FIG. 1 in a zero unit position with the button pressed.

DETAILED DESCRIPTION

FIGS. 1 and 2 show a drug delivery device 1 in the form of an injectionpen. The device has a distal end (lower end in FIG. 1) and a proximalend (upper end in FIG. 1). The component parts of the drug deliverydevice 1 are shown in FIG. 3 in more detail. The drug delivery device 1comprises an outer housing part 10, an inner body 20, a piston rod 30, adriver 40, a nut 50, a display member 60, a button 70, a cartridgeholder 80 for receiving a cartridge 81, a clutch 90, a clicker 100, aspring 110, a cap 120 and a window insert 130. A needle arrangement (notshown) comprising a needle hub and a needle cover may be provided asadditional components, which can be exchanged as explained above. Thepiston rod 30 comprises a bearing 31. The driver comprises a distaldriver part 41, a proximal driver part 42 and a coupler 43. The displaymember 60 comprises a number sleeve 61 and a dial sleeve 62. The clickercomprises a distal clicker part 101, a proximal clicker part 102 and aspring 103.

The outer housing part 10, which is shown in FIG. 4, is a generallytubular element having a distal part 11 for attaching the inner body 20and a proximal part, which is provided with a rotational hard stop 12 onits inner surface (not shown) which contact mating faces of the displaymember 60 when the maximum units (in this example 80U) stop is engaged.The end face also serves as the end of dose dispense stop for the button70, and the bore in the end face centers the display member 60 duringboth dialing and dispense. An aperture 13 is provided for receivingwindow insert 130. The outer body 10 provides the user with a surface togrip and react against during dispense.

The inner body 20 is a generally tubular element having differentdiameter regions. As can be seen in FIGS. 17 to 19, the inner body 20 isreceived in the outer body 10 and permanently fixed therein to preventany relative movement of the inner body 20 with respect to the outerbody 10. The inner body has the functions to house the drive mechanismwithin, guiding the clickers and the last dose nut 50 via internalsplines, to provide an internal thread through which the piston rod 30(lead screw) is driven, to support and guide the number sleeve 61 andthe dial sleeve 62 on an external thread form, to secure the cartridgeholder 80 and to secure the outer body 10 and the window insert 130.

The outermost diameter of the inner body 20 also forms part of thevisual design and remains visible when the cap 120 is secured to thecartridge holder 80 as a ring separating the cap 120 from the outer body10. This visible ring also has depressions which align with the cap snapfeatures on the cartridge holder 80 to indicate that the cartridgeholder has been correctly fitted.

An external thread 21 is provided on the outer surface of the inner body20. Further, splines 22 (FIG. 5 b) are provided on the inner surface ofthe inner body 20. These internal splines 22 guide the proximal part ofthe clicker 102 axially during both dialing and dispense and alsoprevent the last dose nut 50 from rotating. Some of the splines may bewider to ensure correct rotational assembly of the internal components,and these wider splines may have a stepped entry to encourage the lastdose nut 50 which has mating chamfered external ribs to rotate upagainst the stop face on the distal drive sleeve 41 during assembly. Atthe open end shown in FIG. 5 b there are additional short splines whichtogether with the alternating long splines 22 are used to rotationallylock the button 70 (dose dial grip) at the end of dispense and serve toincrease the strength of the 0U dial stop when the button 70 isdepressed. This is achieved by engagement with male spline features 94on the clutch component 90.

Bayonet features 23 guide the cartridge holder 80 into the mechanismduring cartridge replacement, compressing the cartridge bias spring 110,and then back off the cartridge holder 80 a small distance in order toreduce axial play in the mechanism. Snap features inside the inner body20 lock the cartridge holder 80 rotationally when it has been correctlyfitted. The profile of these snaps aims to prevent the user frompartially fitting the cartridge holder 80, the cartridge bias spring 110ejecting the cartridge holder 80 if the snaps have not at least startedto engage. A window retention nose 24 retains the window insert 130 whenthe outer body 10 and window insert 130 assembly is axially insertedonto the inner body 20. Two diametrically opposite stop faces 25 definethe rotational end position for the number sleeve 61. This end positionis the end of dose detent position for the minimum dose (0U).

The piston rod 30 is an elongate element having two external threads 32,33 with opposite hand which overlap each other. One of these threads 32engages the inner thread of the inner body 20. A disk-like bearing 31 isprovided at the distal end of the piston rod 30. The bearing 31 may be aseparate component as shown in FIG. 3 or may be attached to the pistonrod 30 as a one-piece component via a predetermined breaking point.

The piston rod 30 transfers the dispense load from the driver 40 to thebearing 31, creating a mechanical advantage greater than 1:1 byconverting the torque generated on the piston rod 30 by the driver 40thread interface into additional axial load as the piston rod passesthrough the thread in the inner body 20. The piston rod 30 is reset bypressing on the bearing 31 and this in turn rotates the piston rod backinto the inner body 20. This disengages and then rotates the distaldrive sleeve 41, resetting the last dose nut 50 back to its startingposition on the distal drive sleeve 41.

The driver 40 is a generally tubular element having in the embodimentshown in the Figures three components which are depicted in FIGS. 9 to11 in more detail.

The distal drive sleeve 41 engages with the piston rod thread 33 todrive the piston rod 30 through the inner body 20 during dose delivery.The distal drive sleeve 41 is also permanently connected to the coupler43 which in turn is releasably engaged through reset clutch features tothe proximal drive sleeve 42. The two halves of the drive sleeve arerotationally and axially connected during dialing and dispense, but arede-coupled rotationally during device reset so that they can rotaterelative to each other.

The external thread 44 engages with the last dose nut 50. The threadform has three stages, a shallow first stage (left hand side in FIG. 9)over which the nut 50 travels to count the majority of the units dialed,a fast stage over which the last dose nut moves rapidly axially prior toengaging the stop faces, and a final shallow section which ensures thatwhen the stop faces have engaged, the axial restraint on the nut 50extends over a reasonable length of thread form. Four equi-spaced stopfaces 45 engage with mating stop faces 51 on the last dose nut 50 tolimit the number of units that can be dialed. Splines 46 are provided atthe proximal end of distal drive sleeve 41 to transfer torque from or tothe coupler 43, which may be snapped on the distal drive sleeve 41.

The proximal drive sleeve 42 shown in FIG. 10 supports the clickercomponents 100 and the clutch 90 and transfers rotational movement fromthe dose button 90 to the coupler 42 and distal drive sleeve 41.

Teeth features 47 located at the distal end of proximal drive sleeve 42engage with the reset clutch features on the coupler 43 to connect bothhalves of the drive sleeve during dialing and dispense. During resetthese teeth 47 disengage.

Several splines are provided on the outer surface of proximal drivesleeve 42 engaging with distal clicker part 101, preventing relativerotation during dialing and dispense. Further splines, which are locatedin the middle region of proximal drive sleeve 42, engage with the clutch90 component. They may be arranged to be non-rotationally symmetric sothat the various clicker components cannot be assembled accidentallyupside down.

The proximal portion of proximal drive sleeve 42 has four arms orfingers 48. A hook-like bearing surface 49 exists on the underside (asseen in FIG. 10) of flange segments on the end of the flexible fingers48. The flexible fingers 48 are separated with gaps or slots that makespace for the button 70 to snap to the clutch 90 and also enable thesefingers to flex inwards during assembly of the proximal drive sleeve 42to the dial sleeve 62. After assembly the hooks 49 retain the proximaldrive sleeve 42 relative to the dial sleeve 62 under the reaction forcefrom the spring 103. During dispense the button 70 depresses the spring103 via the clutch 90 and the clicker components and this spring 103 isreacted through the coupler 43 to the proximal drive sleeve 42 whichthen through these bearing surfaces applies axial load to the dialsleeve 62. This axial load drives the dial sleeve 62 and hence numbersleeve 61 along the helical thread of the inner body 20, back into thebody of the device, until the 0U stop faces on the number sleeve 61contact the inner body 20.

The coupler 43 shown in FIG. 11 rotationally couples the two halves ofthe drive sleeve together during dialing and dispense, whilst allowingthem to de-couple during reset. The coupler 43 has to also transfer thelast dose protection stop load from the proximal drive sleeve 42 to thedistal drive sleeve 41. Two sets of teeth are provided in the coupler 43for engaging teeth 46 and teeth 47, respectively. The coupler 43 issnapped onto distal drive sleeve 41 allowing limited relative axialmovement with respect to the proximal drive sleeve 42.

The nut 50 is provided between the inner body 20 and the distal drivesleeve 41 of driver 40. Stop faces 51 are located on the proximal faceof last dose nut 50 to limit the number of units that can be dialed ifthe stop faces 51 contact stops 45 of distal drive sleeve 41. Thefunction of the last dose nut 50 is to prevent the user from dialingbeyond a finite amount. This limit is based on the dispensable volume ofthe cartridge 81 and when reached, the user must replace the cartridge81 and reset the device.

External ribs 52 of the nut 50 engage splines 22 of inner body 20. Aninternal thread 53 of the nut engages the external thread 44 of distaldrive sleeve 41. As an alternative, splines and ribs could be providedon the interface between the nut 50 and the driver 40 and threads couldbe provided on the interface between the nut 50 and the inner body 20.As a further alternative, the nut 50 may be designed as e.g. a half nut.

The display member 60 is a generally tubular element which is composedof number sleeve 61 and dial sleeve 62 which are snapped together duringassembly to axially and rotationally constrain these two components,which thus act as a single part.

The main functions of the number sleeve 61 depicted in FIG. 8 are toprovide a surface onto which dose numbers can be printed to display thedialed dose, to guide the helical path of the internal mechanism duringdialing to follow the helical thread form on the piston rod 30 whenthreaded to the inner body 20 and to attach to the dial sleeve 62.Thenumber sleeve 61 is designed to be fully enclosed in the outer body 10during dialing and dispense and therefore only the dialed dose isvisible to the user through the window aperture. The number sleeve has a0U (minimum dose) stop face 63 to limit its travel when dialed in butthe 80U (maximum dose) stop faces that limit the dialed out conditionare located on the dial sleeve 62. At the end of each dispense stroke,this stop face 63 engages with mating surface 25 on the inner body 20 tolimit the rotational position of the number sleeve 61.

A helical drive face 64 forms a thread that guides the number sleeve 61during dialing and dispense to follow the helical path 21 on the innerbody.

The dial sleeve 62 is assembled to the number sleeve 61 such that onceassembled, no relative movement is allowed. The parts are made asseparate components to enable both molding and assembly. Also, whereasthe number sleeve 61 is preferably white to give contrast for the e.g.black dose numbers, the dial sleeve 62 color can be chosen to suit theaesthetics or perhaps to distinguish the drug type.

At the proximal end, the dial sleeve 62 has internal clutch features 65that engage with the clutch component 90 during dialing and disengagefrom the clutch during dispense. These clutch features 65 rotationallylock the dial sleeve 62 to the clutch 90 during dialing and when the 0Uand 80U stops are engaged. When the button 70 is depressed these clutchfeatures disengage to allow the clutch 90 and drive mechanism to moveaxially whilst the dial sleeve 62 and number sleeve 61 spin back to the0U start position.

The dial sleeve 62 rotates out during dialing through its engagementwith the clutch 90 and number sleeve 61, and rotates back in duringdispense under the axial force applied by the proximal drive sleeve 42to a flange-like bearing face 66 on the end of the dial sleeve. Thisbearing face 66 engages with the flexible arms 48 of the proximal drivesleeve 42 during dispense. Two diametrically opposite faces 67 engagewith the outer body 10 when the maximum dose (e.g. 80U) has been dialed,forming the maximum dose stop faces.

A ratchet arm 68 engages with ratchet features on the button 70 (dosedial grip) to provide audible feedback during dispense, giving one clickper unit delivered. Further, this prevents the user from gripping androtating the number sleeve 61 outwards from a partially dialed outposition whilst holding the button 70 pressed in. This would back windthe piston rod 30 which would result in an under dose on the subsequentdialed dose. It may further strengthen the 0U stop.

The button 70 which is shown in FIG. 16 serves as a dose dial grip andis retained by the clutch 90 to transfer the actions of the user to theclutch. It also carries ratchet teeth 71 that engage the ratchet arm 68on the dial sleeve 62, which serves as the dispensing clicker givingaudible feedback (ratchet clicks), and an end face 72 which serves asthe dose completion stop face with the outer body 10. This end face 72thus serves to define the end position during dispense when it contactsthe outer body 10 to provide a very positive stop improving doseaccuracy.

A central sleeve-like portion of button 70 is provided with four arms 73having hook-like snap features 74 at their respective distal ends. Thearms 73 form splined surfaces engaging with the clutch 90 to transfertorque from the button 70 through the clutch to the dial sleeve 62 andproximal drive sleeve 42. The snap features 74 engage apertures in theclutch 90 and are designed with angled undercut faces to maintainengagement when an axial load is applied to pull the button 70 out ofthe pen body 10. The space between arms 73 defines pockets givingclearance for the flexible arms 48 of proximal drive sleeve 42 to slidefreely relative to the button 70 and clutch 90 when the button 70 isdepressed and released during dose dispense.

The cartridge holder 80 attaches to the inner body 20 with a bayonetconnection 82 and houses the glass ampoule or cartridge 81 containingthe medication to be dispensed. The cartridge holder 80 includes anaperture 83 in the rear face (as seen in FIG. 6) which if gripped by theuser prevents the ampoule from falling out when the cartridge holder isremoved from the inner body 20. The front face is printed with a dosenumber scale. The threaded distal end 84 is used to attach disposablepen needles.

A tubular clutch 90 is provided between the display member 60 and thebutton 70. The clutch is fixed relative to and retains the button 70 andtogether they travel axially relative to the proximal drive sleeve 42when the button 70 is depressed during dispense, disengaging the clutchteeth from the dial sleeve 62. It also transfers torque from the buttonto the proximal drive sleeve 42, and the dialing and 0U/80U stop loadsfrom the button via the clutch teeth to the dial sleeve and numbersleeve.

Drive sleeve splines 91 provided on an inner surface of the clutchengage with the proximal drive sleeve 42. At the distal end face, clutchbiasing teeth 92 are provided which mate with similar teeth 109 on theproximal clicker part 102 to ensure that in the button out position(dialed dose) the clutch is locked in rotation to the proximal clickerpart 102 under the biasing action of the clutch spring 103. The teeth 92are shallow in height to prevent the proximal clicker part 102 fromengaging with splines on the proximal drive sleeve 42 during dialing.Four snap apertures 93 serve to retain the snap features 74 of button70. Near its proximal end, the clutch has splines 94 which at the end ofdispense with the button 70 depressed lock to the inner body 20 toprevent the user from rotating the button 70 below the 0U position.

Clutch teeth 95 engage with clutch teeth 65 of the dial sleeve torotationally couple the button 70 via the clutch to the number sleeve61. During dispense the clutch is moved axially so as to disengage theseclutch teeth 95 releasing the dial sleeve 62 to rotate back into thedevice whilst the clutch 90 and hence driver 40 move axially to dispensethe dose.

The clicker 100 comprises a distal clicker part 101, a proximal clickerpart 102 and a spring 103. The clutch spring 103 serves to bias thebutton 70 out so that at the end of a dose the button 70 pops out,re-engaging the clutch 90 with the dial sleeve 62 ready for dialing.Further, it provides the spring force for the clicker components to actas clickers and also as detent positions for the number sleeve 61. Inaddition, it holds the two halves of the drive sleeves 41, 42 inrotational engagement during dialing and dispense, whilst allowing themto disengage during device reset.

The distal clicker part 101 is permanently splined to the proximal drivesleeve 42 and engages with the proximal clicker part 102 which in turnis splined to the inner body 20. During dialing when the drive sleeve isrotated relative to the inner body, the two clickers 101, 102, rotaterelative to each other under the compression force of the clutch spring103. This force combined with the clicker teeth formed on the end faceof each clicker provides the clicks and also the detent dialingpositions.

During dispense the two clickers 101, 102 are pressed together under thedispense load and therefore prevent relative rotation between theproximal drive sleeve 42 and inner body 20, driving the piston rodforwards to deliver the dose. The splines 104 on the inner borerotationally couple the distal clicker part 101 to the proximal drivesleeve 42 at all times, but allow free axial movement when the button 70is depressed during dispense and when the two clickers ride over eachother during dialing. The profile of the clicker teeth 105, 106 on bothdistal clicker part 101 and proximal clicker part 102 are identical andride over each other under the compressive load from the spring 103during dialing.

The proximal clicker part 102 is permanently splined to the inner body20 by external splines 107 which prevent relative rotation with theinner body during both dialing and dispense, providing clicks duringdialing and locking the proximal drive sleeve 42 in rotation duringdispense. Additional cylindrically shaped splines 108 also couple theproximal clicker part 102 rotationally to the proximal drive sleeve 42when the button 70 is depressed, this preventing the user from dialingpast 80 units with the button depressed. Proximal clicker part 102, inaddition to the primary clicker teeth 106, has clutch biasing teeth 109on the opposite end face. These teeth mate with similar teeth 92 on theclutch to ensure that in the button out position (dialed dose) theclutch is locked in rotation to the proximal clicker part 102 under thebiasing action of clutch spring 103.

The cartridge bias spring 110 is assembled as two components one afterthe other, the lower first and the upper second. The spring combinationserves to apply an end load to the cartridge 81 at extremes of toleranceso as to bias it forwards onto the end face of the ferrule in thecartridge holder 80. This ensures that when the user removes andattaches a needle, the friction between the needle cannula and septum ofthe cartridge does not move the cartridge 81 axially relative to thecartridge holder 80. The bias spring 110 also acts to provide a forceagainst which the user has to connect the cartridge holder 80 and thismay add to the tactile feedback of this bayonet joint. The spring 100also serves to eject the cartridge holder 80 if the cartridge holder isnot rotated into a secure position, highlighting this error to the user.

The cap 120 serves to protect the cartridge holder 80 from damage andthe cartridge 81 itself from dust dirt ingress on to the area around theseptum. The cap is designed to accommodate a standard pen injectorneedle.

The window insert 130 may include a lens to magnify the dose numberse.g. by approximately 25% from their printed size. The window insert 130may be back printed to protect the printed surface from abrasion andalso to maximize the light entering through the window aperture, givinguniform illumination of the dose numbers and white area around thesenumbers. Arrows may be printed adjacent to the window aperture thatindicate the dose dialed.

In the following, the function of the drug delivery device and itscomponents will be explained in more detail with reference to FIGS. 17to 19.

To use the device, a user has to select a dose. In the start (at rest)condition as shown in FIG. 17 the display member 60 indicates the numberof doses dialed to the user. The number of dialed units can be viewedthrough the dose window 130 in the outer body 10. Due to the threadedengagement between the display member 60 and the inner body 20 rotationof the button 70 in a clockwise fashion causes the display member 60 towind out of the device and incrementally count the number of units to bedelivered. FIG. 18 shows an intermediate stage of dialing (e.g. 7 of 80units).

During dose setting button 70, driver 40 and display member 60 arerotationally locked together via clutch 90. Further, button 70, driver40 and display member 60 are axially coupled. Thus, these threecomponents wind out of the outer housing 10 during dose setting.Clockwise rotation of the button 70 causes the driver 40 to rotate andin doing so it advances along the piston rod 30 which remains fixedthroughout dialing. The clicker arrangement 100 provides tactile andaudible feedback to the user when dialing doses. At the maximum settabledose of 80 units, the stop features 12 and 67 engage to prevent furtherdialing.

The last dose nut 50 provides the function of counting the number ofdispensed units. The nut 50 locks the device at the end of cartridgelife and as such no more drug can be dialed by the user. The last dosenut 50 and the driver 40 are connected via a threaded interface asexplained above. Further, the last dose nut 50 is assembled into splines22 such that the nut 50 and the inner body 20 are rotationally lockedtogether (at all times). Rotation of the driver 40 during dialing causesthe nut 50 to advance along the thread 44. The nut 50 is free to slideaxially within the inner body 20 at all times which allows advancementof the nut. The change in pitch of thread 44 shown in FIG. 9 towards thefinal doses axially accelerates the advancement of the nut 50 towardsthe end of cartridge life lockout condition. At the end of lifecondition, the stop features 51 of the last dose nut 50 contact thecorresponding features 45 on the driver 40. The splined contact withinner body 20 reacts any torque transmitted by these stop features 45.

With the desired dose dialed, the device 1 is ready for dose dispensing.This basically requires pushing button 70 which will result in adisengagement of the clutch 90 from dial sleeve 62 thus allowingrelative rotation between the display member 60 and the button 70. Inall conditions the driver 40 and the button 70 are rotationally lockedtogether by engagement of arms 73 and fingers 48 and by splines 91engaging corresponding splines on proximal drive sleeve 42. Thus, withthe clutch 90 disengaged (button 70 pushed in) button 70 and driver 40are rotationally locked together with the button 70, the driver 40 andthe display member 60 still being axially coupled.

When dispensing a dose, the dose button 70 and clutch 90 are movedaxially relative to the mechanism compressing the clutch spring 103.Because the proximal clicker part 102 is splined to the inner body 20and the axial load passing through the clicker teeth 105, 106 locks thedistal clicker part 101 in rotation to the proximal clicker part 102,the mechanism is forced to move axially whilst the dial sleeve 62 andnumber sleeve 61 are free to spin back into the outer housing 10. Theinteraction of mating threads between the piston rod 30, driver 40 andinner body 20 delivers a mechanical advantage of 2:1. In other words,axially advancing driver 40 causes the piston rod 30 to rotate which dueto the threaded engagement of piston rod 30 with the inner body 20advances the piston rod. During dose dispensing dispense clicker 68, 71is active which involves button 70 and display member 60. The dispenseclicker provides primarily audible feedback to the user that drug isbeing dispensed.

The end of this step is shown in FIG. 19. At this point the dose iscomplete and when the user removes the force from the end of the dosebutton 70, the clutch spring 103 pushes this dose button 70 rearwards,re-engaging the teeth 65 and 95 between the clutch and the dial sleeve.

Resetting the device starts with removal of the cartridge holder 80 andreplacing an empty cartridge with a full cartridge 81. As the cartridgeholder is re-attached, the bung of the new cartridge contacts bearing31, thus pushing piston rod 30 back into the housing. Initially, thepiston rod 30 screws into the inner body 20, thereby axially disengagingthe coupler 43 from the proximal drive sleeve 42 against the biasingforce of spring 103. Once disengaged the coupler 43 is free to startrotating together with distal drive sleeve 41 and continues to do so asthe cartridge holder 80 is moved axially into engagement with the innerbody 20.Thus, the distal drive sleeve 41 rotates with respect to theproximal drive sleeve 42 which is still rotationally constrained ininner body 20 as clicker parts 101 and 102 are pressed together bycompressed spring 103. As the distal drive sleeve 41 rotates, last dosenut 50 is reset to its (distal) start position. Coupling the cartridgeholder 80 to inner body 20 backs off the mechanism due to the bayonetstructure 23 allowing re-engagement of the proximal drive sleeve 42 withcoupler 43 and thus the distal drive sleeve 41.

1-15. (canceled)
 16. A reusable drug delivery device for selecting anddispensing a number of user variable doses of a medicament, comprising ahousing, a cartridge holder for retaining a cartridge containing themedicament, a piston rod displaceable relative to the cartridge holder,a driver coupled to the piston rod, a display member for indicating aset dose and being coupled to the housing and to the driver, a clutchfor rotationally coupling the driver to the housing or the displaymember and a button rotationally coupled to the clutch and to thedriver, wherein the drug delivery device comprises at least two of thefollowing features: the driver is in threaded engagement with the pistonrod, permanently rotationally locked to the button, axially displaceablerelative to the button and comprises at least two separate componentswhich are rotationally coupled during dose setting and during dosedispensing and which are rotationally decoupled during resetting of thedevice, the display member has a distal end provided with an inwardlyprotruding thread and a proximal end provided with an inwardlyprotruding flange, wherein the display member comprises two separatecomponents with a first component comprising the thread and the othercomponent comprising the flange, the button comprises fingers whichengage corresponding slots of the driver for rotationally coupling thebutton to the driver and which comprise snap features engagingcorresponding snap features of the clutch for axially coupling thebutton to the clutch, the driver comprises fingers which engagecorresponding slots of the button for rotationally coupling the buttonto the driver and which comprise hook features engaging correspondingcontact features of the display member for axially coupling the driverto the display member, the button comprises a ring of clicker teethengaging a corresponding clicker feature of the display member at leastduring dose dispensing.
 17. The drug delivery device of claim 16,wherein the piston rod is in threaded engagement with the housing suchthat the piston rod is rotated during dose dispensing and duringresetting of the device.
 18. The drug delivery device of claim 16,wherein the piston rod is a double threaded piston rod having a firstouter thread engaging an internal thread of the housing and a secondouter thread engaging an internal thread of the driver, wherein thefirst and second outer threads overlap each other at least partially.19. The drug delivery device of claim 18, wherein the first and secondouter threads have the same pitch.
 20. The drug delivery device of claim16, wherein the piston rod comprises a bearing attached to the pistonrod by at least one predefined breakage point, wherein in the bearing isaxially constrained but rotatable with respect to the piston rod afterdetachment of the bearing by destroying the at least one predefinedbreakage point.
 21. The drug delivery device of claim 16, wherein thedriver is a tubular element having a distal portion engaging a nutinterposed between the housing and the driver, and a proximal portionwhich at least partly surrounds a tubular portion of the button.
 22. Thedrug delivery device of claim 16, the driver comprises a first componentwhich is in threaded engagement with a nut and a second component, thefirst and the second component being operatively coupled together, suchthat when a user sets a dose by rotating the button, both the firstcomponent and the second component of the driver rotate together, andsuch that when a user resets the device, the first component of thedriver is decoupled from the second component of the driver and thefirst component is allowed to rotate with respect to the housing andwith respect to the second component.
 23. The drug delivery device ofclaim 16, wherein the driver is in threaded engagement with a nut, andwherein the threaded engagement comprises a helical groove having afirst pitch provided along a first portion of the driver, a second pitchprovided along a second portion of the driver wherein the first pitch issmaller than the second pitch, and optionally a third pitch providedalong a third portion of the driver wherein the third pitch is smallerthan the second pitch.
 24. The drug delivery device of claim 22, whereinthe nut is part of a dose limiter for preventing the setting of a dose,which exceeds the amount of liquid left in a cartridge of the drugdelivery device.
 25. The drug delivery device of claim 16, furthercomprising a clicker having a first toothed element rotationallyconstrained to the housing, a second toothed element rotationallyconstrained to the driver and a spring biasing the first toothed elementand the second toothed element into engagement.
 26. The drug deliverydevice of claim 16, wherein the housing comprises an inner body and anouter body and a window attached to the housing by first retaining meansof the inner body and second retaining means of the outer body.
 27. Thedrug delivery device of claim 16, wherein the housing comprises an innerbody and an outer body and wherein the inner body comprises at least oneinner spline which is helically twisted.
 28. The drug delivery device ofclaim 16, wherein the housing comprises an inner body and an outer bodywith a first rotational stop provided between the inner body and thedisplay member and a second rotational stop provided between the outerbody and the display member limiting the rotational movement of thedisplay member relative to the housing between a minimum dose defined bythe first rotational stop and a maximum dose defined by the secondrotational stop.
 29. The drug delivery device of claim 16, whereinduring dose setting the button is rotated which entrains the driver andthe display member such that the button, the driver and the displaymember are moved on a helical path with respect to the housing and thepiston rod, and wherein during dose dispensing the button is axiallydisplaced which entrains the driver and the display member such that thebutton, the driver and the display member are axially moved with respectto the housing and the piston rod, with the display member and thepiston rod rotating with respect to the housing, the button and thedriver.
 30. The drug delivery device of claim 16 further comprising acartridge containing a medicament.